Process for the preparation of 4-amino-5-fluoro-3-chloro-6-(substituted)picolinates

ABSTRACT

4-Amino-5-fluoro-3-chloro-6-(substituted)picolinates are prepared from trifluoroacetic acid, p-methoxyaniline, a 3,3-dialkoxyprop-1-yne and a substituted methylene amine by a series of steps.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/736,835 filed Dec. 13, 2012, and the benefit ofU.S. Non-Provisional application Ser. No. 14/104,197 filed on Dec. 12,2013, now allowed, the disclosure of which is expressly incorporatedherein by reference.

FIELD

Provided herein are processes for the preparation of4-amino-5-fluoro-3-halo-6-(substituted)picolinates. More particularly,provided herein are processes for the preparation of4-amino-5-fluoro-3-chloro-6-(substituted)picolinates from a non-pyridinesource.

BACKGROUND

U.S. Pat. Nos. 6,784,137 B2 and 7,314,849 B2 describe inter alia certain4-amino-3-chloro-5-fluoro-6-(aryl)picolinate compounds and their use asherbicides. U.S. Pat. No. 7,432,227 B2 describes inter alia certain4-amino-3-chloro-5-fluoro-6-(alkyl)picolinate compounds and their use asherbicides. Each of these patents describes the manufacture of4-amino-3-chloro-5-fluoropicolinate starting materials by fluorinationof the corresponding 5-unsubstituted pyridines with1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]loctanebis(tetrafluoroborate). Each of these patents also describes themanufacture of 6-(aryl)-4-aminopicolinates from coupling reactionsinvolving picolines having either a facile leaving group or a metalderivative in the 6-position of the picoline ring. It would beadvantageous to produce4-amino-5-fluoro-3-chloro-6-(substituted)picolinates without having torely on metal-assisted couplings. It would be advantageous to produce4-amino-5-fluoro-3-chloro-6-(substituted)picolinates efficiently and inhigh yield from a non-pyridine source. It would also be advantageous toproduce 4-amino-5-fluoro-3-chloro-6-(substituted)picolinates withouthaving to rely on direct fluorination of the 5-position of the pyridinering with an expensive fluorinating agent like1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]loctanebis(tetrafluoroborate).

SUMMARY

Provided herein are processes for the preparation of4-amino-5-fluoro-3-chloro-6-(substituted)picolinates from a non-pyridinesource without a metal assisted coupling and without fluorination withan expensive fluorinating agent like1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]loctanebis(tetrafluoroborate). More particularly, provided herein are processesfor the preparation of a4-amino-5-fluoro-3-chloro-6-(substituted)picolinate of the Formula I

wherein

-   -   R¹ represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenyl        substituted with from 1 to 4 substituents independently selected        from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or        C₁-C₄ haloalkoxy, and    -   R² represents C₁-C₁₂ alkyl or an unsubstituted or substituted        C₇-C₁₁ arylalkyl, which comprises the following steps:

a) contacting trifluoroacetic acid with p-methoxyaniline in the presenceof a triarylphosphine and a trialkylamine base in carbon tetrachloridesolvent to produce an acetimidoyl chloride of Formula A

b) contacting the acetimidoyl chloride of Formula A with a3,3-dialkoxyprop-1-yne (Formula B)

wherein R³ represents C₁-C₄ alkyl,

in the presence of copper (I) iodide, an alkali metal iodide and analkali metal phosphate in a polar aprotic solvent to produce an(imino)pent-2-yne dialkyl acetal of Formula C

wherein R³ is as previously defined;

c) cyclizing the (imino)pent-2-yne dialkyl acetal of Formula C with anamine of Formula D

wherein R¹ is as previously defined,

in the presence of an inorganic alkali metal base in a polar aproticsolvent at a temperature from about ambient to about 100° C. to producea 4-(4-methoxyphenyl)amino-5-fluoro-6-(substituted)pyridine-2-dialkylacetal of Formula E

wherein R¹ and R³ are as previously defined;

d) chlorinating the4-(4-methoxyphenyl)amino-5-fluoro-6-(substituted)pyridine-2-dialkylacetal of Formula E with1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (Formula F)

in a polar solvent to produce the protected4-amino-5-fluoro-3-chloro-6-(substituted)pyridine-2-dialkyl acetal ofthe Formula G

wherein R¹ and R³ are as previously defined;

e) deprotecting and hydrolyzing the protected4-amino-5-fluoro-3-chloro-6-(substituted)pyridine-2-dialkyl acetal ofthe Formula G with a mineral acid in a polar solvent to produce the4-amino-5-fluoro-3-chloro-6-(substituted)picolinaldehyde of the FormulaH

wherein R¹ is as previously defined;

f) oxidizing the4-amino-5-fluoro-3-chloro-6-(substituted)picolinaldehyde of the FormulaH with an alkali metal chlorite in the presence of an inorganic acid anda hypochlorous acid scavenger in an aqueous alcoholic solvent to producea 4-amino-5-fluoro-3-chloro-6-(substituted)picolinic acid of the FormulaJ

wherein R¹ is as previously defined; and

g) esterifying the 4-amino-5-fluoro-3-chloro-6-(substituted)picolinicacid of the Formula J with a compound of the formulaR²X

wherein

-   -   X represents OH, Cl, Br, or I, and    -   R² is as previously defined        to produce a 4-amino-5-fluoro-3-chloro-6-(substituted)picolinate        of Formula I.

Another embodiment is a compound of Formula C

wherein R³ represents C₁-C₄ alkyl.

Another embodiment is a compound of Formula E

wherein

-   -   R¹ represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenyl        substituted with from 1 to 4 substituents independently selected        from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or        C₁-C₄ haloalkoxy, and    -   R³ represents C₁-C₄ alkyl.

Another embodiment is a compound of Formula G

wherein

-   -   R¹ represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenyl        substituted with from 1 to 4 substituents independently selected        from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or        C₁-C₄ haloalkoxy, and    -   R³ represents C₁-C₄ alkyl.

Another embodiment is a compound of Formula H

wherein

-   -   R¹ represents C₁-C₄ alkyl, cyclopropyl, C₂-C₄ alkenyl or phenyl        substituted with from 1 to 4 substituents independently selected        from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or        C₁-C₄ haloalkoxy.

DETAILED DESCRIPTION

The terms “alkyl” and “alkenyl,” as well as derivative terms such as“alkoxy,” as used herein, include within their scope straight chain andbranched chain moieties.

The term “arylalkyl,” as used herein, refers to a phenyl substitutedalkyl group having a total of 7 to 11 carbon atoms, such as benzyl(—CH₂C₆H₅), 2-methylnaphthyl (—CH₂C₁₀H₇) and 1- or 2-phenethyl(—CH₂CH₂C₆H₅ or —CH(CH₃)C₆H₅). The phenyl group may itself beunsubstituted or substituted with one or more substituents independentlyselected from halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogenated C₁-C₆ alkyl, halogenated C₁-C₆ alkoxy, C₁-C₆ alkylthio,C(O)OC₁-C₆ alkyl, or where two adjacent substituents are taken togetheras —O(CH₂)_(n)O— wherein n=1 or 2, provided that the substituents aresterically compatible and the rules of chemical bonding and strainenergy are satisfied.

Unless specifically limited otherwise, the term “halogen,” as well asderivative terms such as “halo,” refers to fluorine, chlorine, bromineand iodine.

The phenyl groups substituted with from 1 to 4 substituentsindependently selected from halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy or C₁-C₄ haloalkoxy may be of any orientation, but 4-substitutedphenyl, 2,4-disubstituted phenyl, 2,3,4-trisubstituted phenyl,2,4,5-trisubstituted phenyl, and 2,3,4,6-tetrasubstituted phenyl isomersare preferred.

4-Amino-5-fluoro-3-chloro-6-(substituted)picolinates are prepared fromtrifluoroacetic acid, p-methoxyaniline, a 3,3-dialkoxyprop-1-yne and asubstituted methylene amine by a series of steps.

In step a), trifluoroacetic acid is reacted with p-methoxyaniline andcarbon tetrachloride in the presence of a triarylphosphine and atrialkylamine base to produce2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride. While oneequivalent of p-methoxy-aniline is required for each equivalent oftrifluoroacetic acid, it is often convenient to use an excess of theaniline, typically a 10 to 20% excess. A similar excess of trialkylaminebase is also preferred. It is often convenient to use a much largerexcess of triarylphosphine, typically in the range of a 2 to 4 foldexcess. Carbon tetrachloride, while serving as a reactant, is alsoconveniently used as a solvent for the initial reaction. The reaction isexothermic and it is convenient to control the exotherm by externalcooling and the controlled addition of a carbon tetrachloride solutionof p-methoxyaniline to a mixture of trifluoroacetic acid, trialkylamineand triarylphosphine in carbon tetrachloride. After the initial exothermsubsides, the reaction mixture is generally heated to reflux until theconversion is complete.

In a typical reaction, a mixture of about 3 equivalents oftriphenylphosphine and trifluoroacetic acid in carbon tetrachloride iscooled to about 0° C. in an ice bath and a 20% excess of triethylamineis added. With continued cooling, about a 20% excess of p-methoxyanilinein carbon tetrachloride is slowly added. After completion of theaddition, the mixture is heated to about 70° C. for several hours. Aftercooling, the reaction mixture is extracted with hexane and the solventevaporated to provide crude2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride.

In step b), the 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chlorideis coupled with a 3,3-dialkoxyprop-1-yne in the presence of copper (I)iodide, an alkali metal iodide and an alkali metal phosphate in a polaraprotic solvent to produce anN-(5,5-dialkoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-4-methoxyaniline.While one equivalent of 3,3-dialkoxyprop-1-yne is required for eachequivalent of acetimidoyl chloride, it is often convenient to use anexcess of the 3,3-dialkoxyprop-1-yne, typically a 10 to 20% excess.Similarly, a 10 to 20% molar excess of alkali metal iodide and alkalimetal phosphate are generally preferred. While the reaction is catalyticin copper (I) iodide, usually about 0.1 to about 0.3 equivalents areemployed. The coupling reaction is conducted in a polar aprotic solventat a temperature from about 40° C. to about 100° C. Preferred polaraprotic solvents include ethers like tetrahydrofuran, esters like ethylacetate, nitriles like acetonitrile, amides like N,N-dimethylformamideand N-methylpyrrolidinone and sulfoxides like dimethyl sulfoxide.Anhydrous solvents are preferred with anhydrous acetonitrile beingespecially preferred.

In a typical reaction, 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoylchloride and a slight excess of 3,3-diethoxyprop-1-yne are mixed withabout 0.3 equivalents of copper (I) iodide and slight excesses ofpotassium phosphate and potassium iodide in anhydrous acetonitrile. Themixture is heated at about 60° C. under a nitrogen atmosphere until thereaction is complete. After cooling, an extraction solvent like ahalogenated hydrocarbon is added to the mixture along with water. Theorganic layer is recovered, washed with brine and dried. The solvent isevaporated to provide crudeN-(5,5-diethoxy-1,1,1-trifluoro-pent-3-yn-2-ylidene)-4-methoxyaniline.

In step c), theN-(5,5-diethoxy-1,1,1-trifluoro-pent-3-yn-2-ylidene)-4-methoxyaniline isreacted with a methylene amine substituted with an alkyl, cyclopropyl,alkenyl or (substituted)phenyl group in the presence of an inorganicalkali metal base in a polar aprotic solvent to produce a4-(4-methoxyphenyl)amino-5-fluoro-6-(substituted)pyridine-2-dialkylacetal. While one equivalent of substituted methylene amine is requiredfor each equivalent of N-(5,5-diethoxy-1,1,1-trifluoro-pent-3-yn-2-ylidene)-4-methoxyaniline, it isoften convenient to use an excess of the substituted methylene amine,typically a 2 to 4 fold excess. Suitable inorganic alkali metal basesinclude the lithium, sodium, potassium and cesium salts of hydroxides,carbonates and phosphates. Cesium carbonate is particularly preferred.In general, it is convenient to use a 2 to 4 fold excess of theinorganic alkali metal base.

Preferred polar aprotic solvents include ethers like tetrahydrofuran,esters like ethyl acetate, nitriles like acetonitrile, amides likeN,N-dimethylformamide and N-methylpyrrolidinone and sulfoxides likedimethyl sulfoxide. Anhydrous solvents are preferred with anhydroustetrahydrofuran and dimethyl sulfoxide being especially preferred. Thereaction is typically conducted at a temperature from about ambient toabout 100° C.

In a typical reaction,N-(5,5-diethoxy-1,1,1-trifluoro-pent-3-yn-2-ylidene)-4-methoxyaniline ismixed with about a 2.5 to 3 fold excess of p-chlorobenzylamine and abouta 2.5 to 3 fold excess of cesium carbonate in anhydrous tetrahydrofuran.The mixture is heated at about 80° C. until the reaction is complete.After cooling, an extraction solvent like a halogenated hydrocarbon isadded to the mixture along with water. The organic layer is recovered,washed with brine and dried. The solvent is evaporated to provide crude2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxyphenyl)pyridin-4-amine.

In step d), the4-(4-methoxyphenyl)amino-5-fluoro-6-(substituted)pyridine-2-dialkylacetal is chlorinated with1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in a polar solvent at atemperature from about ambient to about 100° C. to produce4-((3-chloro-6-(substituted)-2-(dialkoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone.While one equivalent of1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione is required for eachequivalent of4-(4-methoxyphenyl)amino-5-fluoro-6-(substituted)pyridine-2-dialkylacetal, it is often convenient to use an excess of the1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione, typically a 2 to 4fold excess. The chlorination is conveniently performed in a mixture ofa polar solvent such as acetonitrile with water.

In a typical reaction, crude2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxyphenyl)pyridin-4-amineis treated with two equivalents of1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in anacetonitrile/water mixture. The mixture is stirred at ambienttemperature until the reaction is complete. The solid product iscollected by filtration, washed with additional acetonitrile/watermixture and dried, providing crude44(3-chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone.

In step e), the4-((3-chloro-6-(substituted)-2-(dialkoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienoneis treated with a mineral acid in a polar solvent at a temperature fromabout ambient to about 100° C. to produce a4-amino-5-fluoro-3-chloro-6-(substituted)picolinaldehyde. Suitablemineral acids include sulfuric and phosphoric acids with sulfuric acidbeing preferred. The mineral acids are usually used as aqueoussolutions. Approximately one equivalent of mineral acid is required buta 10 to 30% excess is preferred. The deprotection/hydrolysis isconveniently performed in a mixture of a polar solvent such asacetonitrile with water.

In a typical reaction,4-((3-chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienoneis treated with a 1 M (molar) solution of sulfuric acid in a mixture ofacetonitrile/water. The mixture is heated at reflux until the reactionis complete. The mixture is added to methylene chloride, and the organiclayer is separated, washed with brine and dried. The solvent isevaporated to provide crude 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinaldehyde.

In step f), the 4-amino-5-fluoro-3-chloro-6-(substituted)picolinaldehydeis oxidized with an alkali metal chlorite in the presence of aninorganic acid and a hypochlorous acid scavenger in an aqueous alcoholicsolvent to produce a 4-amino-5-fluoro-3-chloro-6-(substituted)picolinicacid. While one equivalent of sodium chlorite is required for theoxidation of the aldehyde to the carboxylic acid, it is often convenientto use 2-8 equivalents. The oxidation occurs in mixtures of water withorganic solvents such as acetonitrile or t-butyl alcohol under slightlyacidic conditions (pH 3-5), achieved by the addition of 2-10 equivalentsof inorganic acid salts such as disodium hydrogen phosphate. To avoidunwanted reactions from the hypochlorous acid formed during theoxidation, 2-30 equivalents of a scavenger such as 2-methyl-2-butene,resorcinol or sulfamic acid is added.

In a typical reaction,4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinaldehyde is oxidizedwith an excess of sodium chlorite, between 20-30 equivalents of2-methyl-2-butene and about 5 equivalents of disodium hydrogen phosphatein a t-butyl alcohol/water mixture. The mixture is heated at about 80°C. until the reaction is complete. After cooling, the mixture is treatedwith dilute hydrochloric acid and extracted with ethyl acetate. Theorganic layer is separated and dried. The solvent is evaporated toprovide crude 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinicacid.

In step g), the 4-amino-5-fluoro-3-chloro-6-(substituted)picolinic acidis esterified. Esters of the picolinic acids are prepared by coupling ofpicolinic acid with an alcohol using any number of suitable activatingagents such as those used for peptide couplings such asdicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI) or byreacting the corresponding acid with an appropriate arylalkyl alcohol inthe presence of an acid catalyst. Alternatively, the esters can beprepared by reacting the picolinic acid with an alkyl or arylalkylhalide in the presence of a base. These procedures are well known toorganic chemists and are described, for example, in U.S. PatentApplication Publication 2012/0190551 A1.

In a typical reaction,4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinic acid is reactedwith a slight excess of benzyl bromide and about 2 equivalents ofpotassium carbonate in a polar aprotic solvent such as dimethylsulfoxide or N,N-dimethylformamide. Benzyl4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinate is recovered bypartitioning the reaction mixture between ethyl acetate and water,separating and drying the organic phase and evaporating the solvent.

The products obtained by any of these processes, can be recovered byconventional means, such as evaporation or extraction, and can bepurified by standard procedures, such as by recrystallization orchromatography.

The described embodiments and following examples are for illustrativepurposes and are not intended to limit the scope of the claims. Othermodifications, uses, or combinations with respect to the compositionsdescribed herein will be apparent to a person of ordinary skill in theart without departing from the spirit and scope of the claimed subjectmatter.

EXAMPLES Example 1 2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidoylChloride

A mixture of triphenylphosphine (34.6 grams (g), 132.0 millimoles(mmol)), 2,2,2-trifluoroacetic acid (3.37 milliliters (mL), 44 mmol),triethylamine (7.38 mL, 53.0 mmol) and carbon tetrachloride (21.33 mL,220.0 mmol) was magnetically stirred while cooled with an ice bath.After 10 minutes (min), p-methoxyaniline (6.53 g, 53.0 mmol) dissolvedin carbon tetrachloride (21.33 mL, 220.0 mmol) was addedslowly(exothermic). The ice bath was removed and the reaction mixturewas stirred at reflux for 4 hours (h). Upon cooling to room temperature,the reaction mixture was washed with hexane (3×100 mL). Solvent wasremoved using a rotary evaporator to give 9.8 g of an orange oil.Distillation gave 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoylchloride (9.31 g, 39.2 mmol, 89% yield) as a light yellow liquid: by75-77° C./0.3 mmHg; ¹H NMR (400 MHz, CDCl₃) δ7.31 (m, 2H), 6.96 (m, 2H),3.84 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ159.56 (s), 135.45 (s), 127.98(q), 124.35 (s), 117.05 (q), 114.25 (s), 55.50 (s).

Example 2N-(5,5-Diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-4-methoxyaniline

To a magnetically stirred solution of2,2,2-trifluoro-N-(4-methoxyphenyl)-acetimidoyl chloride (2.376 g, 10.00mmol) and 3,3-diethoxyprop-1-yne (1.538 g, 12.00 mmol) in acetonitrile(20 mL) was added a ground-up mixture of copper(I) iodide (0.571 g, 3.00mmol), potassium phosphate (2.55 g, 12.0 mmol) and potassium iodide(1.660 g, 10.00 mmol). After heating under nitrogen at 60° C. for 16 h,the reaction mixture was added to methylene chloride (CH₂Cl₂; 100 mL)and water (50 mL). The organic layer was washed with a saturatedsolution of sodium chloride (NaCl) and dried (magnesium sulfate; MgSO₄),and the solvent was removed leaving 3.35 g of a yellow liquid. Flashchromatograhy on silica gel eluting with 5% ethyl acetate (EtOAc)/hexanegaveN-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-4-methoxyaniline(2.75 g, 8.18 mmol, 82% yield) as a yellow liquid: ¹H NMR (400 MHz,CDCl₃) δ7.46 (m, 2H), 6.93 (m, 2H), 5.41 (s, 1H), 3.84 (s, 3H), 3.63 (m,4H), 1.22 (m, 6H); ¹³C NMR (101 MHz, CDCl₃) δ160.00 (s), 139.55 (s),134.98 (s), 134.59 (s), 124.65 (s), 113.98 (s), 94.64 (s), 91.21 (s),74.83 (s), 61.55 (s), 55.50 (s), 15.00 (s); ¹⁹F NMR (376 MHz, CDCl₃)δ-70.91 (s); HRMS-ESI (m/z) [M+H]⁺ calcd for C₁₆H₁₈F₃NO₃, 329.1239;found, 329.1225.

Example 32-(4-Chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxyphenyl)pyridin-4-amine

A magnetically stirred solution ofN-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-4-methoxyaniline(0.659 g, 2 mmol), p-chlorobenzyl amine (0.850 g, 6.00 mmol) and cesiumcarbonate (1.629 g, 5.00 mmol) in anhydrous tetrahydrofuran (THF; 10 mL)was heated at 100° C. in the microwave for 8 h. The reaction mixture wasadded to ether (100 mL) and water (50 mL). The organic layer was washedwith a saturated solution of NaCl and dried (MgSO₄), and the solvent wasremoved leaving 1.42 g of a yellow solid. Flash chromatography on silicagel eluting with 10% EtOAc/hexane gave2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxyphenyl)pyridin-4-amine(0.689 g, 1.600 mmol, 80% yield) as an off-white solid: mp 110-111° C.;¹H NMR (400 MHz, CDCl₃) δ7.90 (dd, J=8.5, 1.4 Hz, 2H), 7.43 (m, 2H),7.18 (m, 2H), 7.13 (d, J=6.2 Hz, 1H), 6.94 (m, 2H), 6.19 (d, J=3.7 Hz,1H), 5.31 (br s, 1H), 3.84 (s, 3H), 3.73 (m, 2H), 3.57 (m, 2H), 1.22 (t,J=7.1 Hz, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ-150.95; HRMS-ESI (m/z) [M+H]⁺calcd for C₂₃H₂₄ClFN₂O₃, 430.1459; found, 430.1457.

Example 44-((3-Chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone

A mixture of2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxy-phenyl)pyridin-4-amine(0.862 g, 2 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione(0.788 g, 4.00 mmol) in 1:1 acetonitrile/water (20 mL) was stirred atroom temperature. After 2 h, the orange solid was collected byfiltration, washed with 1:1 acetonitrile/water (5 mL), dried at roomtemperature and recrystallized from ether/hexane.4-((3-Chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone(0.272 g, 30% yield) was isolated as orange crystals: mp 134-136° C.; ¹HNMR (400 MHz, CDCl₃) δ7.96 (m, 2H), 7.44 (m, 3H), 6.76 (m, 2H), 6.58(dd, J=10.2, 2.1 Hz, 1H), 5.79 (s, 1H), 3.90 (m, 2H), 3.72 (m, 2H), 1.31(t, J=7.1 Hz, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ-134.18; HRMS-ESI (m/z)[M+H]⁺ calcd for C₂₂H₁₉Cl₂FN₂O₃, 448.0757; found, 448.0761.

Example 5 4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinaldehyde

A mixture of4-((3-chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone(180 milligrams (mg), 0.401 mmol) and 0.1 molar (M) sulfuric acid(H₂SO₄; 0.5 mL) in a 1:1 mixture of acetonitrile/water (4 mL) was heatedto 80° C. for 1 h. After stirring at room temperature for 2 h, thereaction mixture was added to CH₂Cl₂ (20 mL). The organic layer waswashed with a saturated solution of NaCl and dried

(MgSO₄), and the solvent was removed leaving4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinaldehyde (82 mg,0.273 mmol, 68% yield) as an off-white solid: mp 166-169° C.; ¹H NMR(400 MHz, CDCl₃) δ10.12 (s, 1H), 7.96 (m, 2H), 7.48 (m, 2H), 4.99 (s,2H); ¹⁹F NMR (376 MHz, CDCl₃) δ-137.68; ESIMS m/z 285.64 ([M+H]⁺).

Example 6 4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinic Acid

4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinaldehyde (105 mg,0.37 mmol) was dissolved in t-butyl alcohol (2.2 mL). Water (800 μL),2-methyl-2-butene (1.0 mL, 700 mg, 10 mmol), disodium hydrogen phosphate(Na₂HPO₄; 276 mg, 2 mmol) and sodium chlorite (106 mg, 1.2 mmol) wereadded to a crimp seal microwave vial. The reactants were mixed, and thereaction vessel was sealed and heated to 80° C. for 16 h. The reactionmixture was then cooled to ambient temperature, and the mixture wasdiluted with 1 normal (N) hydrochloric acid (HCl; 5 mL) and EtOAc (10mL). After stirring for 5 min, the layers were separated, and theaqueous layer was extracted with EtOAc (4×5 mL). The combined organiclayers were dried (sodium sulfate; Na₂SO₄) and evaporated to dryness toprovide 95 mg of an oily brown solid. The solid was dissolved in aminimum of aqueous 1 N sodium hydroxide (NaOH) and slowly neutralizedwith aqueous 4 N HCl until a white/brown precipitate appeared. Theprecipitate was collected and dried, yielding4-amino-3-chloro-6-(4-chloropheny0-5-fluoropicolinic acid (78 mg, 72%yield): ¹H NMR (400 MHz, CDCl₃) δ8.5 (br s, 1H), 7.96-7.86 (m, 2H),7.59-7.75 (m, 2H), 6.1 (br s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ-141.07;ESIMS m/z 299. 4 ([M−H]⁻).

Example 8 Benzyl 4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinate

4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinic acid (23.1 mg,0.080 mmol) was dissolved in dimethyl sulfoxide (800 μL) in a crimp sealmicrowave vial. Potassium carbonate (23.4 mg, 0.166 mmol) was addedtogether with benzyl bromide (10 μL, 14.4 mg, 0.084 mmol). The reactionvessel was sealed and the reaction mixture was vigorously stirred for 16h at room temperature. The reaction mixture was then partitioned betweenwater (10 mL) and EtOAc (10 mL). The layers were separated, and theaqueous layer was extracted with additional EtOAc (3 mL). The combinedorganic layers were washed with water (3×4 mL), washed with brine (2mL), dried (Na₂SO₄) and evaporated to dryness to provide 26.1 mg ofwhite solid. The crude product was purified using flash columnchromatography using a 4 g ISCO silica column eluted with a gradient of0-100% EtOAc/hexanes over 16 min. The crude product was loaded on thecolumn with a minimum amount of methylene chloride. Benzyl4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoro-picolinate (8.3 mg, 25%yield) was obtained as a light waxy oil: ¹H NMR (400 MHz, CDCl₃)δ7.93-7.91 (s, J=7.3 Hz, 2H), 7.53-7.35 (m, 7H), 5.46 (s, 2H), 4.94-4.87(br m, 2H); ¹⁹F NMR (376 MHz, DMSO) δ-144.88; ESIMS m/z 391. 4 ([M+H]⁺).

What is claimed is:
 1. A compound of Formula C

wherein R³ represents C₁-C₄ alkyl.